Vida Jakovljevic

Effect of stevioside and sodium salt of monoketocholic acid on glycemia in normoglycemic and diabetic rats

SummaryThis study investigated the effect of a commercial preparation of stevioside and a synthetic compound, sodium salt of monketocholic acid (MKC), administered per os (p.o.) and also adminstered via an osmotic pump, on glycemia in normoglycemic and diabetic Wistar rats. Diabetes was induced with alloxan, 100 mg/kg, i.p. Normoglycemic and diabetic rats were treated p.o. for five days either with physiological solution (1 ml/kg, controls), stevioside (20 mg/kg), MKC (4 mg/kg) and a combination of stevioside (20 mg/kg) and MKC (4 mg/kg). Apart from p.o. adminstration, stevioside and MKC were also administered via a subcutaneously (s.c.) implanted osmotic pump. During treatment and upon termination of the latter, glycemia was measured and the rats that were treated p.o. were subjected to the oral glucose tolerance test (OGTT) at a dose of 1 g/kg. Following this animals were anesthetized with urethane (0.75 g/kg, i.p.) and killed by cardiopunction to determine C-peptide levels in the serum. In all three groups of normoglycemic rats highest decrease in glucose levels was observed on the fourth day of the experiment. The stevioside + MKC combination showed a stronger hypoglycemic effect compared to individual treatments with stevioside and MKC (3.73:4.80:4.73 mmol/L). In the group of diabetic rats that received both substances via the osmotic pump, the hypoglycemic action was also stronger compared to the individual treatments with stevioside and MKC (16.15:18.89:18.75 mmol/L). The treatment of healthy rats with both substances p.o. caused no statistically significant difference in glycemia, whereas in diabetic rats the combination of stevioside + MKC showed a statistically significant decrease in glycemia compared to control values. In both groups of rats, treatment with stevioside and MKC and their combination prevented an increase in glucose concentrations in the OGTT. Only the administration of stevioside by osmotic pump yielded a statistically significant increase in the concentrations of C-peptide in the serum of healthy rats. Compared to controls, the concentrations of C-peptide in diabetic rats were significantly higher after treatment with either stevioside or its combination with MKC, irrespective of the mode of administration.

The effect of celery and parsley juices on pharmacodynamic activity of drugs involving cytochrome P450 in their metabolism

SummaryCelery (Apium graveolens) and parsley (Petroselinum sativum), plants used worldwide in human nutrition, are the natural sources of methoxsalen. In this study we investigated the effect of mice pretreatment with juices of this plants on the hypnotic action of pentobarbital and analgesic action of paracetamol and aminopyrine, the drugs involving cytochrome P450 superfamily in their metabolism. In mice pretreated with celery and parsley juices a prolonged action of pentobarbital with respect to control was observed, statistical significance being attained only with parsley-pretreated animals. Both pretreatments increased and prolonged the analgesic action of aminopyrine and paracetamol, pretreatment with parsley being again more effective. Celery and parsley juices given to animals two hours before their decapitation caused a significant decrease of cytochrome P450 in the liver homogenate as compared to control.

Glucose concentration in the blood of intact and alloxan-treated mice after pretreatment with commercial preparations of Stevia rebaudiana (Bertoni).

SummaryThe study was concerned with the effect of mice pretreatment with two commercial products of Stevia rebaudiana Bertoni on the blood glucose concentration. One group of mice was pretreated four days with 200 mg/kg of Stevita (Stevita Co, INC, Arlington Texas) (stevia) and the other with 20 mg/kg of Clear Steviosides liquid (Stevita Co, INC, Herbal supplement, Brazil) (stevioside), whereas the animals of control group received at the same time physiological solution. Blood glucose concentration was measured before pretreatment and four days after that. The changes in glucose level were provoked by glucose-tolerance test (500 mg/kg, p. o. ) and subcutaneous injection of adrenaline (0. 2 mg/kg). The same procedure of measuring blood glucose was applied on the mice with alloxan-induced diabetes mellitus (two doses of 100 mg/kg with a 24-hour interval).Blood glucose levels in mice pretreated with stevia and stevioside were lower compared with control (7. 82: 6. 82: 8. 01). Also, a smaller increase in this parameter compared to control was registered with pretreated mice in thw glucose-tolerance test, pretreatment with stevioside being again more effective (8. 68: 6. 36: 5. 82). Pretreatment with stevioside being caused no significant increase in blood glucose concentration after administering adrenaline, which was not the case with the animals pretreated with stevia and control. Pretreatment with stevia, and to a greater extent with stevioside, protected test animals from the toxic action of alloxan compared with controls.

Drug utilization in paediatrics: Non-medical factors affecting decision making by prescribers

SummaryThe study was done to show that in certain areas of paediatric pharmacotherapy unexpected discrepancies may arise between accepted therapeutic principles and the actual behaviour of a prescribing doctor. The first example was of a great reduction in penicillin use in a university teaching hospital after certain therapeutic accidents: in one year, there were 2 fatal cases of rhabdomyolysis due to use of procaine benzyl-penicillin. Other antimicrobial drugs inferior to penicillin, such as lincomycin and sulphonamides, replaced penicillins. The second example showed the inverse relationship between the use of antitussives and other drugs in symptomatic treatment of respiratory diseases in outpatients and inpatients; the pressure of unduly optimistic expectations of therapy imposes a high prescribing rate of these drugs in the outpatient population, in contrast to hospitalized patients, whose doctors, being spared such pressure, prescribe antitussives far less often. The third example demonstrates the possibility of inadequate education in the use of antimicrobial drugs. Although doctors from regional hospitals receive their training at an university hospital, they tend to prescribe chloramphenicol ten times more per bed-day than their colleagues in an university hospital. In terms of the cost/effectiveness ratio, a high prescribing rate of cephalosporins is not economically favourable in a university teaching hospital. It is also shown that studies of drug utilization in children are feasible if age — appropriate adaptation of the statistical value expressed as the defined daily dose is performed. The adaptation was evaluated by comparing pharmacy-based drug consumption data expressed in “paediatric defined daily doses”, with actual days of treatment with particular drugs, i.e. data from patient records for 244 beds in the University Teaching Hospital.

Anti-oxidative activity of an aqueous suspension of commercial preparation of the mushroom Coprinus comatus.

In this study the effects of an aqueous suspension of a commercial preparation of the mushroom Coprinus comatus on oxidative stress induced in rats by alloxane and carbon tetrachloride was examined. The effects were estimated from changes in the biochemical parameters (xanthine oxidase, glutathione peroxidase and catalase activity, reduced glutathione content, and extent of lipid peroxidation) of liver homogenate as well as histological changes in the liver of the rats treated with alloxane and carbon tetrachloride. Two screening doses of alloxane sufficient to induce diabetes in rats did not have any significant effect on the examined biochemical parameters of liver homogenate or on the cytoarchitectonics of liver cross-sections. Treatment with carbon tetrachloride resulted in a significant increase in the intensity of lipid peroxidation and peroxydasis activity, as well as with decrease in catalase activity. Certain changes in liver cross sections were detected, such is lymphocyte infiltration of dilated sinusoid capillaries. Administration of Coprinus comatus suspension thus showed antioxidative potential, evidenced by an increase of antioxidative status of liver homogenate and prevention of histological changes in liver cross sections.

Effect of rat pretreatment with aqueous solutions of stevioside and bile acids on the action of certain cardioactive drugs

SummaryThe interaction of aqueous solutions of stevioside and bile acids with cardioactive drugs was studied in rats by registering changes in their electrocardiograms (ECG). Wistar rats of both sexes received daily doses of 20 mg/kg (i.p.) of an aqueous solution of stevioside or physiological solution (controls), then were narcotized with urethane and connected to the ECG apparatus for the first recording. The jugular vein was prepared and connected to an infusion pump to administer one of the drugs: adrenaline (0.1 mg/ml), verapamil (2.5 mg/ml) or metoprolol (1 mg/ml) to rats in both groups, while recording their ECGs. In the second part of the study, the animals were treated in the same way but instead of the stevioside solution received a single dose of 4 mg/kg of monoketocholic acid methyl ester (ME) or sodium salt of the same bile acid (MKHNa), 30 minutes before cardioactive drug infusion. The infusion rate of cardioactive drugs was 0.2 ml/min, except for verapamil (0.1 ml/min). The events observed on ECG recordings were the first myocardial reaction to drug infusion, the second longer-lasting reaction (observed as more extended extrasystoles, decrease in intensity of the QRS complex, or changes in heart rate frequency), and toxicity effect. In the control animals, adrenaline induced a decrease in heart rate frequency at a dose of 0.094 mg/kg, while with stevioside-pretreated rats this effect appeared significantly earlier (at a dose of 0.018 mg/kg). No toxic effect of adrenaline was observed, either in control or stevioside-pretreated group. Bile acids caused no changes in myocardial reaction to adrenaline. Only in the group of animals that received MKHNa, a significant decrease in the QRS complex was observed. Finally, the infusion of stevioside to intact animals at doses of 45 and 55 mg/kg caused no significant changes in the ECG patterns. The myocardial reaction to metoprolol remained unchanged in rats of all groups when compared with controls except for a mild decrease in heart rate frequency. Stevioside inducedproduced a significant increase in myocardial sensitivity to verapamil, but no toxic effect was observed in any of the cases. A similar conclusion also holds for the interaction with MKHNa, whereas ME caused an increase in the toxicity of verapamil.

Joint effect of commercial preparations ofStevia rebaudiana Bertoni and sodium monoketocholate on glycemia in mice

SummaryA study was made of the combined effect of two commercial products of Stevia rebaudiana Bertoni and sodium monoketocholate (mkc) on blood glucose concentration in mice. One group of animals was treated four days with mkc, 4 mg/kg, s. c, second with 200 mg/kg, i. p. , of Stevita (Stevita Co, INC, Arlington, Texas) (stevia), third with 20 mg/kg, i. p. , of Clear Steviosides Liquid (Stevita Co, INC, Herbal supplement, Brazil) (stevioside), fourth with the combination of stevia and mkc, and the fifth with stevisode and mkc. Blood glucose concentration was measured before treatment, after the first and fourth dose, as well as after subjecting animals to glucose-tolerance test (500 mg/kg, p. o. ) or provoking glycemia by injecting adrenaline (0. 2 mg/kg, s. c). It was found that one dose of stevioside combined with mkc caused a significant increase of glycemia with respect of mkc alone and control (10. 80:7. 90:8. 01). However, when repeated four days, the same pretreatment resulted in a significant decrease of glycemia compared with single-dose pretreatment (10. 80:7. 20). The increase in glycemia with the mice that received four doses of stevioside and mkc and then were subjected to glucose-tolerance test was significantly lower compared to that in mice that were pretreated four days only with mkc before receiving glucose (6. 33:7. 80). Analogous difference was observed between the animals given mkc alone and mkc plus stevioside after injecting adrenaline ( 13. 33:10. 54). As for the interaction of mkc and stevia it was found that the combined pretreatment yielded lower values of glycemia compared with that measured after treatment with stevia alone (6. 40:7. 82).

Effect of 12-monoketocholic acid on modulation of analgesic action of morphine and tramadol

SummaryThis work is concerned with the potential promotive action of 12-monoketocholic acid (12-MKC) on the analgesic effect of morphine and tramadol. The investigation was carried out on laboratory Wistar rats divided into five test groups, each treated with either morphine (2 mg/kg), tramadol (9.6 mg/kg), 12-MKC (2 mg/kg), morphine + 12-MKC, or tramadol + 12-MKC, the control group receiving physiological solution (2 mg/kg). The effect of 12-MKC on the analgesic action of morphine and tramadol was determined by radiation heat method. Morphine and tramadol, given in equimolar doses, did not show significant difference in the degree of analgesia. In combination with morphine, 12-MKC increased significantly the analgesic effect compared with the group treated with morphine alone. However, 12-MKC caused no change in the action of tramadol. The 5-day intravenous application of 12-MKC in combination with the two analgesics caused no changes in the biochemical parameters nor pathohistological changes in the liver parenchyma of tested animals.

Diclofenac and ketoprofen liver toxicity in rat

SummaryIn the last years there appeared many articles about the adverse influence of non-steroidal anti-inflammatory drugs on the liver and heart. This study is concerned with the influence of the duration of treatment with diclofenac and ketoprofen on the macroscopic and microscopic changes in the liver, lungs, heart, and kidneys in rats. Experiments were carried out on mature Wistar strain rats. Animals of test groups received diclofenac and ketoprofen in a dose of 8 mg/kg/day (equivalent to the therapeutic dose for man) during 7 per os (p.o.) or 28 days intraperitoneally (i.p.), whereas controls received physiological solution p.o. A high morbidity was observed in the animals receiving diclofenac p.o. and somewhat lower in those treated with ketoprofen. On the other hand, the rats got through the 28-day i.p. treatment with both drugs mainly without significant complications. Macroscopic examinations revealed some changes in treated rats: distension of the stomach, ascites, fibrin deposits on the internal organs, lung effusion and the changes in color and structure of the liver. These changes were more frequent in the group of rats receiving diclofenac for the 7 days compared with those that received ketoprofen for the same time. It may be thought that the high mortality and macroscopic changes in the internal organs of experimental animals are a consequence of the microscopic changes in the liver and its lowered function.

The effect of aluminium chloride upon the transition of drugs through the blood-brain barrier into the central nervous system.

SummaryIn order to determine the effect of Al3+ upon the transition of drugs through the blood-brain barrier into the central nervous system we examined its effect upon a drug that dissociates as a cation (quinidine) and drugs that dissociate as anions (acetylsalicylic acid and pentobarbital).The entry and exit of quinidine into and out of the brain in mice pre-treated with AICI3 was inhibited. Al3+ did not compete with acetylsalicylic acid for the penetration through the blood-brain barrier but did slow down its elimination from the brain. Brain kinetics of the examined drugs showed good correlation with their central pharmacodynamic effects.